Salicylic-acid derivative and process of making the same.



in obtaining in a pure state a. hitherto una rns Parana FIFIQE;

LORENZ AGE AND TI-IEODOR SUTTER, OF MANNHEIM, GERMANY, ASSIGNORS TO (3.F. BOEHRINGER & SOEHNE, OF MANNHEIM-WALDHOF, GERMANY.

SALICYLIC-ACID DERIVATIVE AND PROCESS MAKING THE SAME.

Specification of Letters Patent.

Patented May 25, 1909.

Application filed May 20, 1908.- Serial No. 433,859. (Specimens) b allwhom it may concern:

Be it known that we, LORENZ Aer-I and Tnnonon SUTTER, citizens ofGermany and Switzerland, respectively, residing at Mannheim, Germany,have invented certain new and useful Iniprovements in Salicylic-Acid 3Derivatives and the Process of Making the Sallie; and we do herebydeclare the following to be a full, clear, and exact description of theinvention, such as will enable others skilled in the art to which itappertains to make and use the same. I

The object of the present invention is to I obtain a substitute forsalicylic acid which, among other things, is adapted for thcra- 1,pcutic use in the place of the same.

In the literature relating to this art a large number of experimmrtsvand attempts have been described which all have for their object the premration of salicylic acid anhydrid from sa licylic acid or itscompounds. These experiments have resulted in a variety of productswhich may be classed as neutral and acid products in vidw of theirbehavior in the presence of alkalies and alkaline carbonates iii thecold. The first group of compounds have been. studiedand examined inrecent times by Anschiitz (see Licbig Ann. 275 vp. 80.6) and by Einhorn(see Ber'ichte 34, p. 2951) and others. They have reported methods forobtaining pure crystalline compounds such as for example, disalicylid,tctrasalicylid or polysalicylid. All these com )()U11(lS are obtainedfrom salicylic acid by the separation of one molecule of water from onemolecule of salicylic acid. When these experiments did not involve sogreat a splitting oil of water there have been obtained products havingacid properties and in the form of unsatisfactory amorphous masses whosechemical composition was not constant and which were formed by theaggregation of several molecules of salicylic acid in chain-likegroupings (see Be'iZste/t'n Vol. II p. 1498). In our experiments andresearches in this field we have succeeded known acid anhydrid ofsalicylic acid which is formed of two molecules of acid by the splittingoil of one molecule of water therefrom. This body we have obtained in amanner to assure a good yield and as a distinct compound by the actionof condensing agents on salicylic acid, or a salicylate. This newanhydrid melts at from 147 to 148 C.

and has the empiric formula 0 11 0 and the structural formulao,n,.on.co.o.c n,.ooon

and it is therefore properly designated as salicylo-salicylic acid.

The properties of this new compound are very marked. In coldalcohol andether, the same is soluble only with ditliculty, but

i is readilysoluble in these bodies when heated. It is soluble in about6.5 parts by weight of boiling benzene and is immediately thrown out ofsuch solution on cooling in the form of coarse crystals, suchprecipitation being almost complete. These properties serve todistinguish the present new compound in a very striking manner from theamorphous substances referred to in Be'ilste'i'n Vol. II, p. 1498 underthe name of salicylo salicylic acid.

The new anhydrid is soluble in water only with extreme difficulty, evenwhen boiling the'saine. On the other hand, it is very readily dissolvedin cold aqueous solutions of alkalies. On acidifying such solutions itis again precipitated unchanged. The new compound is modified by heatingthe same to a temperature near its melting point for a sustained periodof time and by condensing agents. 7

The new product may be obtained in suflicient yield if the necessaryprecautions are taken, that during the course of the reaction thesalicylo-salicylic acid is not further changed as it is produced. Inorder to attain this end it is necessary to guard against too extensivea condensation and for this purpose various conditions inust bemaintained according to the nature of the condensing agent and thestarting material. I

In connection with the condensing agent the various properties of thesame are to be considered such as its volatility and rapidity with whichit reacts.

We have found that one may use only so much of the condensing agent asis necessary to split off one molecule of water from two molecules ofthe starting material which may be salicylic acid or a neutral or basicsalicylate 1'. e. a compound of salicylic acid with an inorganic or anorganic base, such for instance, as pyridin or dialkylanilin. In manycases this checking action is aided by maintaining the temperature at alow point. In many cases also it is advantageous though the not strictlynecessary to dilute the mixture of reagents with solvents such as forinstance the aromatic hydrocarbons among which are to be mentioned inarticular benzene and toluene. The salicy ic-salicylic acid thusobtained incrystalline form is tasteless and free from any irritatingaction on the stomach and it is readily and completely split up in theintestine. It is, therefore, exceedingly well adapted to take the placeof salicylic acid as a medicine.

The following examples will serve to elucidate my invention.

Exam le 1: A solution of5 parts by weight of salicy ic acid in 5.2 partsof dimethyl anilin and 1.5 arts benzene is prepared, and into this a soution of one part by weightof phosphorus-trichlorid in 1.5 parts ofbenzene is introduced in drops while stirring and while maintaining thewhole cool by the circulation of water at ordinary tem erature. Themixture thus obtained is a owed to stand for several days at ordinaryatmospheric temperature. Thereuplon the mass is introduced into anexcess of ydrochloric acid of substantially 12% strength whileconstantly stirring the mass. Several hours after the completion of thistreatment the crystalline mixture of salicylic acid andsalicylo-salicylic acid which is formed is separated from the bath bysiphoning or otherwise removing the liquid portion and by boiling thesaid crystal line mass with water. By this latter treatment thesalicylo-salicylic acid is directly obtained in the form of coarsecrystals having a melting point of from 147 to 148 C. These crystals arefound to be chemically pure.

/ The reaction which takes place in forming the new compound isexpressed in the following equation:

Example 2: 5 parts by weight of salicylic acid are dissolved in 4.4parts by weight of dimethyl anilin, and into this solution 1 part byweight of phosphorus-trichlorid is slowly introduced in drops, thesolution being constantly cooled and stirred during the introduction ofthe condensing agent. After allowing the mixture so prepared to standfor several days at atmospheric temperature the same is made to undergothe further treatment described under Example 1.

Example 3: Into a solution of 10 parts by weight of salic lic acid in 12parts by weight of dimethy -anilin and 10 parts by weight of benzenewhich is maintained cool by circulation of water, a solution of twoparts by weight of phosphorus-trichlorid in 8 parts by weight of benzeneis introduced dropwise while stirring the whole. The mixture is allowedto stand from ten to twelve hours at atmospheric temperature andthereafter it is heated to about C.

and maintained at this temperature for from one to two hours. To thismass there is then added an excess of a saturated solution of sodiumcarbonate in an amount sufficient for complete combination with thecondensation product whereupon the water layeris separated fromthebenzene-dimethy anilin solution. The sodium solution is nowacidified, whereupon the resultant salicylosalicylic acid precipitatesin the form of a quickly solidifying mass. This precipitation takesplace at the commencement of the acidification, while at the 'end ofthis treatment the excess of salicylic acid is thrown out. Theprecipitate is then boiled with water and the solid residuum isdissolved in benzene. From this solution the salicylic acid anhydrid orsalicylo-salicylic acid is obtained in pure state.

Example4 A solution of 14 parts by weight of salicylic acid and 12 partsby weight of dimethyl-anilin in 25 parts by weight of benzene isprepared and cooled by means of ice. Into this cooled solution there isintroduced slowly a 10 solution of two parts by weight of phosgene(carbonylchlorid, 0001,) in benzene, care being taken that atmosphericmoisture is excluded. After allowing this mixture to stand atatmospheric temperature for from ten to twelve hours the dimethyl anilinis eliminated from the same by extraction with an aqueous acid solution.The separated benzene solution is stirred with an amount of sodiumcarbonate solution not suflicient for complete neutralization. By thismeans the new salicylic acid anhydrid which is dissolved in the benzenesolution may be freed from salicylic acid which remains in aqueoussolutions. The new anhydrid is obtained from the benzene solution bydistilling off the benzene.

Exam le 5 A mixture of 14 parts by Weight of salicy '0 acid with 12parts by weight of dimethyl anilin is maintained cool and into thismixture is introduced a solution of 3 parts by weight of phosphorusoxychlorid in 10 parts by weight of benzene. After having allowed themass to stand for 12 hours at ordinary temperature the same is furthertreated as described in Example'4.

Example 6: 10 parts by weight of salicylic acid are mixed with 10 partsby weight of dimethyl anilin, and to thls mixture is slowly added asolution of 3 parts by weight of thionylchlorid SOCl in 5 parts byweight of toluene, while cooling with ice and stirring. The rest of thetreatment proceeds as in Examples 4 and 5.

lli

Example 7 14 parts by weight of salicylic acid are dissolved in 18 partsby weight of pyridin (C H N) and cooled with ice and during such cooling4 parts of phosgenc dissolved in a solution of benzene is added whilestirring the whole. This mixture is then allowed to stand for twelvehours at ordinary temperature, whereupon it is heated on the water bathfor one or two hours and thereupon further treated as in Example 4.

Example 8: 1 part by weight of thoroughly dried, finely powdereddipotassium salicylate (C I-LOILCOOK) is suspended in from 3 to 4 partsof benzene and phosgene is rapidly introduced into this. mixture. Heatis liberated and an almost clear solution results. This solution is thencooled,.where upon potassium-chlorid is thrown out. The new salicylicacid anhydrid is then extracted by means of a sodium-carbonate solutionand the extract is then purified as in Example 4:-

Example 9: 1-0 parts by weight of dry mono-sodium salicylate (tF'H,,.OH.COONa) are suspended in 10 parts by weight of benzone and tothis mixture two parts by weight of .phosphorus oxychlorid are addedslowly while well stirring. The temperature is then slowly raised to 50C. and the mass is maintained at this temperature for four hours whilestirring. After filtering the solution is treated as in Example 3.

Example 10: 10 parts by weight of salicylic acid are suspended in 10parts by weight of toluene and boiled with reflux cooling together with2 parts by weight of phosphorus oxychlorid for five hours. The resultantmass is then treated with sodium carbonate solution and the extract soformed treated as above for purification.

It will be seen from the above examples, that under this invention astarting compound containing the salicylic acid radical, such assalicylic acid or a salicylate, is acted on by a condensing agent, suchas hosphorus trichlorid, hosphorus-oxych orid, phosgene or thionyl-cilorid, such condensing agent'being present in quantities less than anexcess of the amount necessary to split off one molecule of water fromtwo molecules of the said starting com ound. Moreover it is to be notedthat it is preferable to dilute, that is to say, to suspend or todissolve such starting compound in a suitable solvent, preferably anorganic solvent, such as benzene, toluene, a mixture of the same with analkyl-ariilin, or other solvent aromatic hydrocarbon compound, althoughsuch dilution 1s not indispensable. It is also preferable tocool thereaction mixture to produce the new anhyd rid.

The yield in carrying out the process varies considerably in thedifferent examples. We have been able to obtain as high as 80%.

What we claim and desire to secure by Letters-Patent is 1. Theprocess'which consists in submitting a startirw compound containing thesalicylic acid radical to the action of a condensing agent, in aquantity not exceeding the a nount necessary to split otl' onemoleculeof water from two molecules of the salicylic acid radical.

The process which consists in sub1nitting salicylic acid to theaction ofa condensing agent in a quantity not exceeding the amount necessary tosplit off one molecule of water from each two molecules of the salicylic acid.

b. The process which consists in submitting a starting compoundcontaining the salicylic acid radical together with a diluting agent tothe action of a condensing agent not in excess-of the quantity necessaryto split oil one molecule of water from each two molecules of thesalicylic acid radical.

4. The process which consists in submitting salicylic acid together witha diluting agent to the action of a condensing agent not in excess ofthe quantity necessary to split ofl' one molecule of water from each twomolecules of the salicylic acid radical.

5. The process which consists in submit ting a starting compoundcontaining the saiicylic acid radical in solution to the action of acondensing agent in a quantity not in excess of the amount necessary tosplit otl' one molecule of water from each two molecules of the startingcompound.

6. The rocess which consists in submitting salicylic acid in solution tothe action of the condensing agent in a quantity not in excess of theamount necessary to split otl' one molecule of water from each twomolecules of the salicylic acid.

7. The process which consists in subniitting a starting compoundcontaining the salicylic acid radical together with an organic solventof such compounds to the action of a condensing agent not in excess ofthe amount. necessary to split oil one molecule of water from each twomolecules of said starting compound. v

8. The process which consists in submitting salicylic acid together withan organic solvent of the same to the action of a con (lensing agent,said condensing agent being added in quantities not. in excess of theamount necessary to split ofl' one molecule of water from each twomolecules ol' tho salicylic acid,

9. The process which consists in submitting a starting compoundcontaining the salicylic acid radical together with a hydrocarbonsolvent of the aromatic series to the action of a condensing agent, saidcondensing agent being added in quantities not in excess of the amountnecessary to split oli one molecule of water from each two molecules ofsalicylic acid.

10. The process which consists in submitting a starting compoumlcontaining the salicylic acid radical together with benzene anddimethyl-ani-lin to the action of a condensing agent, said condensingagent being added in quantities not in excess of the amount necessary tosplit off one molecule of water from two molecules of the startingcompound.

11. The process which consists in submitting a starting compoundcontaining the salicylic acid radical and dimethyl-anilin diluted withbenzene to the action of a quantity of phosphorus-trichlorid not inexcess of the amount necessary to split olf one molecule of water fromtwo molecules of the starting compound, allowing the mixture to standfor a sustained period of time, and then adding a hydrochloric acidsolution to throw out the resultant salicylic acid anhydrid mixed withan excess of salicylic acid.

12. The process of separating salicylic acid anhydrid having the formulagiven above from salicylic acid which consists in boiling the mixture ofthe two with water.

13. The process which consists in submitting a starting compoundcontaining the salicylic acid radical to the action of a condensingagent in quantity not in excess of the amount necessary to split off onemolecule of water from two molecules of the starting compound,separating the mixture of salicylic acid and salicylic acid anhydridthus produced from the bath and boiling said mixture with water.

14. The process which consists in submitting a starting compoundcontaining the salicylic acid radical to the action of a condensingagent not in excess of the quantity necessary to split off one moleculeof water from each two molecules of the starting compound whilemaintaining a low temperature.

15. The process which consists in submitting a starting compoundcontaining the salicylic acid radical in solution to the action of acondensing agent not in excess of the quantity necessary to split offone molecule of water from each two molecules of the starting compoundwhile maintaining a low temperature.

16. As a new chemical compound, a salicylic acid anhydrid Whosecomposition is represented by the structural formula:

and which has the following properties: It is soluble with difliculty incold alcohol or ether, but readily soluble therein under heat; it issoluble in substantially 6.5 parts by weight of boiling benzene andthrown out from such solution in the form of coarse crystals, itsboiling point is 147 to 148 centigrade, in crystalline form it istasteless and partakes of the therapeutic properties of salicylic acid.

In testimony whereof We hereunto afiix our signatures in the presence oftwo witnesses.

LORENZ ACH. THEODOR SUTTER.

Witnesses:

Jos. H. LEUTE, TERESA CATTURANI.

